Alzheimer's Med Falls Short in Down Syndrome Patients

Action Points

Explain that memantine, an NMDA receptor antagonist, was not an effective treatment for cognitive impairment and dementia in Down syndrome patients over 40.

Point out that the study assessed attention, memory, and executive function scales in the Down syndrome patients.

The NMDA receptor antagonist memantine (Namenda) was not an effective treatment for cognitive impairment and dementia in Down syndrome patients older than 40, according to a European study.

In a prospective, randomized trial, both placebo and medication groups had a decline in cognition over the 52 weeks of the study, but there were no significant differences in the Down syndrome attention, memory, and executive function scales (DAMES) scores, reported Clive Ballard, MD, from the Centre for Age-Related Diseases at King's College London, in The Lancet.

After adjustment for baseline scores, there were nonsignificant differences between groups of -4.1 (95% CI -13.1 to 4.8) in the DAMES results, -8.5 in the Adaptive Behavior Scale (ABS) part I scores (95% CI -20.1 to 3.1) and 2 in ABS part II (95% CI -7.2 to 11.3), all in the favor of the controls.

Alzheimer's disease-like features develop in Down syndrome patients by the time they are 40. Because memantine has been shown to have an impact on decline in Alzheimer's patients and in two mice models of Down syndrome, the researchers decided to undertake a trial to determine if the medication had a significant effect on cognitive decline in this population.

In the MEADOWS study, 173 patients with karyotypic or clinically diagnosed Down syndrome were enrolled from four learning disability centers in the U.K. and Norway. They were randomized to receive memantine or to the placebo group.

DAMES has 11 domains with summaries for attention, executive function, and memory with scores between 0 and 222. ABS is informant-based with part I focused on independent functioning and part II for assessing challenging behavior. For DAMES and ABS part I, higher scores are positive. For ABS part II, a high score is indicative of maladaptive behavior.

The enrollees were reassessed at 52 weeks using both ABS scales and the DAMES scores. The trial began on June 20, 2005 with the last follow-up visit occurring Dec. 30, 2008.

Independent functioning, as measured by the ABS part I, deteriorated more in the treatment group (drop of nearly 11 points) at 52 weeks than in the placebo group (a drop of nearly 2 points), although the difference did not reach significance (P=0.15).

There also were nonsignificant changes in challenging behavior on ABS II for the memantine group.

Mean global impression of change scores did not differ between the memantine group and the placebo group at 52 weeks (P=0.21) or 26 weeks (P=0.31), the authors reported, but scores were better in the placebo group than they were in the memantine group at 12 weeks (P=0.02).

The number of deaths or overall serious adverse events did not differ between groups, suggesting that memantine was well tolerated, they said.

Blood tests to assess changes in plasma amyloid-beta showed no effect of treatment. Amyloid beta1-40 concentrations were 195.07 (SD 93.01) for the placebo group and 189.06 (SD 79.73) at 52 weeks for the memantine group (P=0.75). Differences in amyloid beta1-42 concentrations also failed to reach significance at 52 weeks (P=0.44).

The main limitation to the study was that the researchers were only able to recruit 173 of the originally intended 180 participants, which lowered the study's power from 91% to 90%. Because of the numerical differences in the direction of placebo for all outcomes, they doubted that the absence of benefits was not related to the lower power.

"The findings of this study are robust and represent an important step in the evidence base for treatment of people with Down's syndrome with cognitive decline," the authors wrote.

In an accompanying editorial, Gill Livingston, MD, and Andre Strydom, PhD, from the University College London, called the results "disappointing," but the study does help in excluding treatments of little benefit.

"The MEADOWS trial shows that randomized trials are possible in this population and should encourage future trials of potential drugs that are based on strong experimental evidence," they wrote.

Ballard received consultancy and speaking fees from Lundbeck, Janssen, Novartis, and Acadia, and grants from Lundbeck and Acadia.

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